Aldehyde dehydrogenase inhibition combined with phenformin treatment reversed NSCLC through ATP depletion
- Aldehyde dehydrogenase inhibition combined with phenformin treatment reversed NSCLC through ATP depletion
- 이철주; 강준희; 이선형; 이재선; 보아스 남; 성태화; 선재경; 장현철; 홍경만; 김수율
- Issue Date
- VOL 7, NO 31-49410
- Among ALDH isoforms, ALDH1L1 in the folate pathway showed highly increased expression in non-small-cell lung cancer cells (NSCLC). Based on the basic mechanism of ALDH converting aldehyde to carboxylic acid with by-product NADH, we suggested that ALDH1L1 may contribute to ATP production using NADH through oxidative phosphorylation. ALDH1L1 knockdown reduced ATP production by up to 60% concomitantly with decrease of NADH in NSCLC. ALDH inhibitor, gossypol, also reduced ATP production in a dose dependent manner together with decrease of NADH level in NSCLC. A combination treatment of gossypol with phenformin, mitochondrial complex I inhibitor, synergized ATP depletion, which efficiently induced cell death. Pre-clinical xenograft model using human NSCLC demonstrated a remarkable therapeutic response to the combined treatment of gossypol and phenformin.
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